WO2014163031A1

WO2014163031A1 - Instantaneous intestinal regulator

Info

Publication number: WO2014163031A1
Application number: PCT/JP2014/059404
Authority: WO
Inventors: 圭介堰; ナダーシーワナーソン
Original assignee: 株式会社明治
Priority date: 2013-04-01
Filing date: 2014-03-31
Publication date: 2014-10-09
Also published as: SG11201508154QA; HK1217290A1; JPWO2014163031A1; CN105073107A

Abstract

The present invention provides an instantaneous intestinal regulator, which: contains a Propionibacteriaceae culture, DHNA or an analog thereof as an active ingredient; manifests intestine-regulating effects within one day after being taken; and manifests more pronounced intestine-regulating effects within two days after being taken. The present invention also provides an instantaneous intestinal regulator, which contains a Propionibacteriaceae culture, DHNA or an analog thereof as an active ingredient and maintains the intestine-regulating effects for two weeks after being taken.

Description

Fast acting intestinal

The present invention relates to an immediate-acting intestinal agent having a low physical burden unlike conventional intestinal-regulating agents. Specifically, the present invention includes a propionic acid bacteria culture, DHNA (1,4-dihydroxy-2-naphthoic acid) or an analog thereof as an active ingredient. The present invention relates to an immediate-acting intestinal agent with a small physical burden.

In order to eliminate constipation, there is a need for immediate effects (fast-acting properties), and as an immediate-effect constipation drug (laxative), the stool is inflated with moisture to improve the convenience and increase the constipation (increased dose) Have been known for some time, such as those that directly enhance intestinal motility (especially intestinal contractility) (irritant laxatives). These laxatives are used as symptomatic treatments, and those who are prone to chronic constipation need to take (continuously) frequently. However, these laxatives are not suitable for long-term sustained use or ingestion because they cause resistance through continuous use. In addition, these laxatives may cause side effects such as abdominal pain and diarrhea, so the physical burden is large, and it is difficult for the elderly, infants, infants, patients, etc. to take them frequently. is there.

On the other hand, although immediate effects are weak, probiotics (for example, live bacteria such as lactic acid bacteria and bifidobacteria) and prebiotics (for example, indigestible) are used as intestinal preparations that adjust the intestinal environment by ingesting continuously. Oligosaccharides, dietary fibers, sterilized microorganisms, etc.) are known. These intestinal preparations have a mild intestinal effect and are extremely unlikely to cause side effects such as abdominal pain and diarrhea that are problematic with the laxatives described above.

Recently, there are many chronically constipated persons, mainly women and the elderly, and since they are taken or ingested continuously over a long period of time, an intestinal preparation with a low physical burden and a sense of security has been demanded. Preparing the intestinal environment and promoting natural defecation leads to maintenance of health and improvement of QOL, so there is much demand, and some of such effective intestinal preparations are known as functional foods .

For example, Profec (Meiji, trade name; “Profec” is a registered trademark of Meiji Meiji Co., Ltd.) is “tummy vitality tablet (tablet containing Profec)” and “tummy vitality milk (milk drink containing Profec)” (Meiji's “Onaka Vitality” is a commercialized product such as “Meiji Meiji Co., Ltd.”), which is known as prebiotics, and has received approval for foods for specified health use. Profec is a whey fermented product of Propionibacterium freudenreichii ET-3 strain isolated from Emmental cheese and developed as a material containing components that promote the growth of bifidobacteria, among the main enteric bacteria. (Non-Patent Document 1). It has been clarified that when humans ingest Profec in 2 to 4 weeks, the effect of intestinal regulation is exhibited (Non-patent Documents 2 to 4, Patent Document 1). In subsequent studies, DHNA (1,4-dihydroxy-2-naphthoic acid) was identified as the main component involved in the growth promotion of bifidobacteria contained in Profec. It has also been clarified that administration of DHNA to colitis model animals exerts an improvement / prevention effect on enteritis (Non-patent Document 5).

However, in probiotics and prebiotics, (1) in order to develop an intestinal regulating effect, it is necessary to continuously take or ingest (administer) a certain amount of material in one week or more (Patent Documents 2 and 3). ), (2) Among bowel control effects, the effect of improving bowel movement (for example, increase in the number of bowel movements or increase in the volume of bowel movement) is often not recognized significantly (Patent Document 2), (3) bowel movement improvement effect There is a known problem that a person with a tendency to constipation needs to take or ingest (administer) the material continuously. That is, at present, there are few known intestinal regulating agents having both immediate effect, sustainability and safety.

WO2011 / 145737 JP2001-169749 JP2006-104121

An object of the present invention is to provide an intestinal regulating agent that has a low physical burden, is highly safe, has an immediate effect, and is durable.

The present invention is based on the discovery of a new fast-acting and long-lasting intestinal effect related to Profec, which has not been known for a long time.

Up to now, the present inventors have repeatedly examined the intestinal effect of Profec by ingesting Profec for several weeks. As a result, a certain stool improvement effect was observed by taking Profec for 2 to 4 weeks (for example, Non-Patent Documents 3 and 4). In contrast, the present inventors, for the first time, evaluated Profec's intestinal effect over time in a wide range of age groups suffering from constipation. Surprisingly, one day after the start of ingestion of Profec It was found that a significant bowel movement improving effect was exhibited, and a more remarkable bowel movement improving effect was expressed after two days. It was also found that the effect of improving stool does not weaken when Profec is ingested for 2 weeks, and that this effect of improving stool persists for at least 2 weeks after the cessation of Profec.

The basic features and various aspects of the present invention are listed below.
[1] An immediate-acting intestinal regulating agent comprising at least one component of a culture of propionic acid bacteria, or DHNA or an analog thereof.
[2] The immediate-acting intestinal agent of [1], wherein the propionic acid bacterium is Propionibacterium freudenreichii.
[3] The immediate-acting intestinal agent of [1] or [2], which is an immediate-acting stool improving agent.
[4] Any one of [1] to [3], wherein the intestinal regulating effect is obtained within 7 days, preferably within 2 days, more preferably within 1 day after ingestion (after administration) The fast-acting intestinal agent.
[5] The intestinal effect lasts for 1 week, preferably 1.5 weeks, more preferably 2 weeks after the discontinuation of ingestion (administration), [1] to [4] Any of the immediate-acting intestinal agents.
[6] Daily intake (dose) is 5 μg or more (for example, 5 μg to 100 μg), preferably 6 μg or more (for example, 6 μg to 50 μg), more preferably 6.5 μg or more (for example, 6.5 μg to 20 μg), the immediate-acting intestinal agent according to any one of [1] to [5].
[7] The content per packaging form is 5 μg to 100 μg, preferably 6 μg to 50 μg, more preferably 6.5 μg to 20 μg, using the converted amount (content) of DHNA or an analog thereof as an index. The immediate-acting intestinal regulating agent according to any one of [1] to [6].
[8] The rapid-acting intestinal agent according to any one of [1] to [7], which is taken (administered) together with a collagen peptide.
[9] The immediate-acting intestinal agent according to any one of [1] to [8], further comprising a collagen peptide.

The present invention further relates to the following aspects.
[A-1] A method for producing an immediate-acting intestinal preparation comprising a step of blending (using) at least one component of a culture of propionic acid bacteria or DHNA or an analog thereof, preferably propionic acid bacteria Is Propionibacterium freudenreichii, and a fast-acting intestinal preparation is a fast-acting bowel movement improving agent.
[A-2] Immediate effect of [A-1], wherein an intestinal regulating effect is obtained within 7 days, preferably within 2 days, more preferably within 1 day after ingestion (after administration) Method for producing an intestinal preparation.
[A-3] The intestinal effect is sustained for (at least) 1 week, preferably 1.5 weeks, more preferably 2 weeks after cessation of ingestion (administration), [A-1] Or [A-2] a method for producing an immediate-acting intestinal regulating agent.
[A-4] Daily intake (dose) is 5 μg or more (for example, 5 μg to 100 μg), preferably 6 μg or more (for example, for example) using the equivalent amount (intake) of DHNA or an analog thereof as an index. 6 .mu.g to 50 .mu.g), more preferably 6.5 .mu.g or more (for example, 6.5 .mu.g to 20 .mu.g), the method for producing an immediate-acting intestinal agent according to any one of [A-1] to [A-3].
[A-5] The content per packaging form is 5 μg to 100 μg, preferably 6 μg to 50 μg, more preferably 6.5 μg to 20 μg, using the converted amount (content) of DHNA or an analog thereof as an index. A process for producing an immediate-acting intestinal regulating agent according to any one of [A-1] to [A-4].

The present invention further relates to the following aspects.
[B-1] Use of a culture of propionic acid bacteria or DHNA or an analog thereof for the production of a rapid-acting intestinal agent, preferably, the propionic acid bacteria is Propionibacterium freudenreichii And an immediate-acting intestinal preparation is an immediate-acting bowel movement improving agent.
[B-2] Use of [B-1], wherein an intestinal regulating effect is obtained within 7 days, preferably within 2 days, more preferably within 1 day after ingestion (after administration).
[B-3] The intestinal effect is sustained for (at least) 1 week, preferably 1.5 weeks, more preferably 2 weeks after cessation of ingestion (administration), [B-1] Or use of [B-2].
[B-4] Daily intake (dose) is 5 μg or more (for example, 5 μg to 100 μg), preferably 6 μg or more (for example, for example) using the converted amount (intake) of DHNA or an analog thereof as an index. 6 μg to 50 μg), more preferably 6.5 μg or more (for example, 6.5 μg to 20 μg), the use according to any one of [B-1] to [B-3].
[B-5] The content per packaging form is 5 μg to 100 μg, preferably 6 μg to 50 μg, more preferably 6.5 μg to 20 μg, using the converted amount (content) of DHNA or an analog thereof as an index. The use of any one of [B-1] to [B-4].

The present invention further relates to the following aspects.
[C-1] A culture of propionic acid bacteria or DHNA or an analog thereof for use in the expression of an immediate intestinal regulating effect. Preferably, the propionic acid bacteria is Propionibacterium (Propionibacterium). freudenreichii), an immediate effect of bowel control is an immediate effect of improving bowel movement.
[C-2] Propionic acid of [C-1], wherein an intestinal regulating effect is obtained within 7 days, preferably within 2 days, more preferably within 1 day after ingestion (after administration) Fungal culture or DHNA or analogs thereof.
[C-3] The intestinal regulating effect lasts for 1 week, preferably 1.5 weeks, more preferably 2 weeks after cessation of ingestion (administration), [C-1] Or a culture of propionic acid bacteria of [C-2] or DHNA or an analog thereof.
[C-4] The daily intake (dose) is 5 μg or more (for example, 5 μg to 100 μg), preferably 6 μg or more (for example, for example) using the converted amount (intake) of DHNA or an analog thereof as an index. 6 .mu.g to 50 .mu.g), more preferably 6.5 .mu.g or more (for example, 6.5 .mu.g to 20 .mu.g), the culture of propionic acid bacteria of any one of [C-1] to [C-3] or DHNA Or its analogues.
[C-5] The content per packaging form is 5 μg to 100 μg, preferably 6 μg to 50 μg, more preferably 6.5 μg to 20 μg, using the converted amount (content) of DHNA or an analog thereof as an index. A culture of propionic acid bacteria according to any one of [C-1] to [C-4], or DHNA or an analog thereof.

The present invention further relates to the following aspects.
[D-1] A method for producing an immediate intestinal regulating effect, comprising a step of ingesting (administering) an effective amount of at least one component of a culture of propionic acid bacteria or DHNA or an analog thereof. Preferably, the propionic acid bacterium is Propionibacterium freudenreichii, and the immediate effect of intestinal regulation is an immediate effect of improving bowel movement.
[D-2] Immediate effect of [D-1] characterized in that an intestinal regulating effect can be obtained within 7 days, preferably within 2 days, more preferably within 1 day after ingestion (after administration) Of intestinal regulation effect.
[D-3] The intestinal effect lasts for (at least) 1 week, preferably 1.5 weeks, more preferably 2 weeks after cessation of ingestion (administration), [D-1] Or [D-2] a method for producing the immediate effect of intestinal regulation.
[D-4] The daily intake (dose) is 5 μg or more (for example, 5 μg to 100 μg), preferably 6 μg or more (for example, for example) using the equivalent amount (intake) of DHNA or an analog thereof as an index. 6 μg to 50 μg), more preferably 6.5 μg or more (for example, 6.5 μg to 20 μg), exhibiting an immediate intestinal regulating effect of any of [D-1] to [D-3] How to make.
[D-5] The content per packaging form is 5 μg to 100 μg, preferably 6 μg to 50 μg, more preferably 6.5 μg to 20 μg, using the converted amount (content) of DHNA or an analog thereof as an index. A method for producing an immediate effect of regulating intestines according to any one of [D-1] to [D-4].
In [D-1] to [D-5], it is desirable to exclude medical acts (acts requiring a doctor's prescription).

As described above, in general, probiotics and prebiotics have been known as materials that maintain the intestinal environment by continuously ingesting them, thereby producing an intestinal regulating effect. Therefore, they have been recognized as a material for the main purpose and intended use of preventing constipation. A culture of propionic acid bacteria or DHNA or an analog thereof, which is an active ingredient of the immediate-acting intestinal agent of the present invention, was also known as one of the prebiotics. Surprisingly, within one day after ingestion It was revealed for the first time that a bowel movement improving effect was exhibited within a short period of time, and a more remarkable bowel movement improving effect was exhibited within two days after ingestion. On the other hand, the rapid-acting intestinal adjuster of the present invention can be produced by blending ingredients (such as raw materials) that have been ingested (administered) by humans as foods and the like. Therefore, the immediate action intestinal preparation of the present invention has already been guaranteed high safety and can be taken continuously (continuously). Thus, the immediate-acting intestinal agent of the present invention has a plurality of advantageous effects such as the immediate effect of conventional laxatives and the sustainability and safety of conventional probiotics and prebiotics. It has been clarified that it can be provided as a new means with a small physical burden for obtaining an intestinal effect.

It is a graph which shows a test subject's defecation frequency. “*” And “* Δ” indicate that there is a significant difference at p <0.01 and p <0.05, respectively, compared with the second week (Week2). It is a graph which shows a time-dependent change of the average value of a test subject's defecation frequency. “Wm-n” means the n-th day of the m-th week, for example, W3-1 (the first day of the third week) means the first day after taking the test meal. It is a graph which shows a time-dependent change of a test subject's defecation amount. “Wm-n” means the n-th day of the m-th week, for example, W3-1 (the first day of the third week) means the first day after taking the test meal. It is a graph which shows a subject's difficulty of defecation. “*” And “* Δ” indicate that there is a significant difference at p <0.01 and p <0.05, respectively, compared with the second week (Week2). It is a graph which shows the time required for a test subject's defecation. “*” And “* Δ” indicate that there is a significant difference at p <0.01 and p <0.05, respectively, compared with the second week (Week2). It is a graph which shows the change of a test subject's feeling at the time of defecation. “*” And “* Δ” indicate that there is a significant difference at p <0.01 and p <0.05, respectively, compared with the second week (Week2). It is a graph which shows a subject's satisfaction with the frequency of defecation. “*” And “* Δ” indicate that there is a significant difference at p <0.01 and p <0.05, respectively, compared with the second week (Week2). It is a graph which shows a subject's satisfaction to the time required for defecation. “*” And “* Δ” indicate that there is a significant difference at p <0.01 and p <0.05, respectively, compared with the second week (Week2). It is a graph which shows the satisfaction to the characteristic of a test subject's defecation. “*” And “* Δ” indicate that there is a significant difference at p <0.01 and p <0.05, respectively, compared with the second week (Week2). It is a graph which shows a test subject's satisfaction with the defecation habit. “*” And “* Δ” indicate that there is a significant difference at p <0.01 and p <0.05, respectively, compared with the second week (Week2). It is a graph which shows distribution of the days for a test subject to feel the bowel regulation effect. The horizontal axis indicates the number of days after taking the test meal, and the day of intake is the 0th day. For each day after taking the test meal, the bar graph shows the number of subjects who first felt the bowel control effect, and the line graph shows the cumulative percentage of subjects who felt the bowel regulation effect.

Hereinafter, the present invention will be described in detail. However, the present invention is not limited to the following preferred embodiments, and can be freely changed within the scope of the present invention.

The present invention provides a rapid-acting intestinal regulating agent comprising at least one active ingredient of a culture of propionic acid bacteria or DHNA or an analog thereof.

In the present specification, the “intestinal regulating effect” includes a bowel movement improving effect, a constipation improving effect, an intestinal environment improving effect, and a fecal improvement effect, and preferably a bowel movement improving effect. Therefore, in the present specification, the “intestinal regulating agent” includes a bowel movement improving agent, a constipation improving agent, an intestinal environment improving agent, and a fecal improvement agent, and is preferably a bowel movement improving agent. In this specification, “improvement of bowel movement” means increase in the number of bowel movements, increase in the volume of bowel movement, improvement in difficulty of bowel movement, reduction in time required for bowel movement, improvement in feeling during bowel movement, improvement in frequency of bowel movement, bowel movement characteristics Means improvement of stool and / or improvement of defecation habits, and can also be expressed as “facilitation of bowel movement”.

As used herein, “immediate effect” means within 7 days, within 6 days, within 5 days, within 4 days, or within 3 days after ingestion (after administration), preferably within 2 days after ingestion, more Preferably, it means the property of exhibiting a predetermined effect within one day after ingestion, and “expression of immediate effect of intestinal regulation” can also be expressed as “expression of intestinal effect in a short period of time”. . Similarly, “improved in a short period” means within 7 days, 6 days, 5 days, 4 days, or 3 days after ingestion (after administration), preferably within 2 days after ingestion, Preferably, it means improving the condition within one day after ingestion. In the present specification, the term “persistence” means the property of maintaining a predetermined effect for at least 1 week, preferably 1.5 weeks, more preferably 2 weeks after cessation of administration (administration). . Here, “maintaining a predetermined effect” means that the effect after stopping the intake of a predetermined (active) component is 30% or more, preferably 50% or more, more preferably 70% compared to the effect during intake. It means that it is maintained at% or more. In the present specification, “intake” can also be expressed as “administration”.

In the present specification, the term “immediately effective intestinal adjuster” does not mean only pharmaceutical products or quasi-drugs that are used to develop an immediate effective intestinal regulating effect. For example, health supplements, health functions It also means foods (special health foods or functional foods for nutrition), functional foods such as supplements, food additives, and the like.

The quick-acting intestinal preparation of the present invention is characterized by a small physical burden. Therefore, the rapid-acting intestinal regulating agent of the present invention can be used for constipation prone persons of a wide age group. That is, it can be preferably used for women, elderly people, infants, infants, or sick persons (patients) who have been difficult or impossible to use conventional laxatives because the physical burden is not small. The immediate-acting intestinal agent of the present invention can be preferably used by women because it can be expected to improve beauty.

In this specification, “physical burden is small” means that the difficulty of defecation does not deteriorate due to ingestion of a predetermined (effective) component, the frequency of stool, required time, characteristics or satisfaction with habits. It means not decreasing, or the degree or frequency of side effects such as abdominal pain and diarrhea does not increase. Furthermore, “physical burden is small” means that the side effect such as abdominal pain or diarrhea is low or mild or is caused by ingestion of a predetermined (active) ingredient, or is accompanied by such a side effect. It also means no. Therefore, the immediate-acting intestinal preparation of the present invention is preferably an immediate-acting intestinal with a low degree or frequency of side effects, and more preferably an immediate-acting intestinal with no side effects.

In one embodiment, the rapid-acting intestinal regulating agent of the present invention includes a culture of propionic acid bacteria. Propionic acid bacteria are gram-positive anaerobic bacteria belonging to the genus Propionibacterium, and are microorganisms that produce propionic acid oxygen-freely from sugars. Specifically, the rapid-acting intestinal regulating agent of the present invention can be blended (added) with the following microorganism culture. Namely, Propionibacterium freudenreichii, Propionibacterium toeni (P. thoenii), Propionibacterium ashidipropionici (P. acidipropionici), Propionibacterium genseny (P. jensenii) and the like. These propionic acid bacteria are microorganisms used for cheese production. In addition, the following microorganisms can also be shown as propionic acid bacteria. Ie, Propionibacterium avidum (P. avidum), Propionibacterium acnes (P. acnes), Propionibacterium lymphophilum (P. lymphophilum), Propionibacterium granulosum (P. granulosam) is there.

A method for isolating these propionic acid bacteria from nature or fermented milk is known. These propionic acid bacteria may be microorganisms used for manufacturing Swiss cheese and the like. The culture of propionic acid bacteria in the present invention refers to those obtained by culturing the above propionic acid bacteria under appropriate culture conditions. Methods for culturing propionic acid bacteria are known. In the culture of propionic acid bacteria, the conditions described in WO03 / 016544A1 and the like can be applied. For example, if a suitable medium is inoculated with Propionibacterium freudenreichii and cultured under conditions where propionic acid bacteria can grow, a culture of propionic acid bacteria can be obtained.

The rapid-acting intestinal regulating agent of the present invention can be blended with other components (materials, etc.) after sterilizing the culture of propionic acid bacteria after completion of the culture. Alternatively, the immediate-acting intestinal regulating agent of the present invention can be sterilized after blending a culture of propionic acid bacteria with other components (materials, etc.) after completion of the culture. For example, in the case of milk, sterilization methods and the like are stipulated in a ministerial ordinance such as milk, and low temperature long time sterilization, high temperature short time sterilization, and ultra high temperature (instant) sterilization can be used as general heat sterilization treatment. .

The sterilization method equivalent to the case of milk or heat sterilization treatment can be applied to the culture of propionic acid bacteria of the present invention or the immediate action intestinal preparation containing the same. These heat sterilization treatments may be a batch type (batch unit) or a continuous type. At this time, the treatment temperature and treatment time vary depending on the respective heat sterilization treatment, but preferably 60 ° C. to 150 ° C., in the range of 0.1 second to 1 hour, more preferably 70 ° C. to 150 ° C., 0.5 second to 45 minutes. The range is more preferably 80 ° C. to 150 ° C., and the range of 1 second to 30 minutes is selected according to the sterilization method described above. In sterilizing the culture of propionic acid bacteria, it is desirable that the amount of dissolved oxygen in the treatment liquid be kept in a reduced state. Therefore, in the heat sterilization treatment, the culture of propionic acid bacteria or the rapid-acting intestinal regulating agent containing the same is continuously maintained in an inert gas atmosphere and / or injected with an inert gas as necessary ( Bubbling) is preferred. Examples of the inert gas include nitrogen gas, argon gas, carbon dioxide gas, etc., but they are present in large quantities in the air, the cost is relatively low, safety is confirmed, and the flavor and quality of food and drink Nitrogen gas is particularly desirable because it does not affect the process. Alternatively, in the heat sterilization treatment, the culture of propionic acid bacteria or the rapid-acting intestinal preparation containing the same is maintained in a vacuum (reduced pressure) atmosphere and / or allowed to pass through the vacuum atmosphere as necessary. It is preferable. Examples of the vacuum state include reduced-pressure degassing treatment.

The inventors of the present invention have confirmed that an immediate intestinal regulating effect is maintained in the sterilized product of the propionic acid bacteria culture. That is, in the present invention, the immediate effect of intestinal regulation of the culture of propionic acid bacteria is maintained even after sterilization of the culture. Normally, the influence of microorganisms (such as lactic acid bacteria) on the host depends on the action of live bacteria. Probiotics and prebiotics have been reported to improve the intestinal environment and stimulate immunity. In general, probiotics refer to microorganisms that give a beneficial effect to the host by being introduced into the intestine of the host in a living state. In contrast to probiotics, prebiotics refer to substances that have beneficial effects on the host by acting on microorganisms that originally lived in the intestines. For example, several types of microorganisms (such as lactic acid bacteria and bifidobacteria) have been reported as probiotics that exhibit an intestinal regulating action in human tests. However, since these microorganisms function as probiotics and act on live bacteria, their production and quality control have not been easy. Furthermore, in general, live bacteria preparations have limited storage stability. For example, after producing a live bacteria preparation, the original activity (stability) cannot be maintained over a long period even if stored at a low temperature. There were many.

Compared to probiotics such as live bacteria of conventional microorganisms (such as lactic acid bacteria and bifidobacteria), the culture of propionic acid bacteria of the present invention not only functions as probiotics but also functions as prebiotics. To do. At this time, in the sterilized product (prebiotic) of the culture of the propionic acid bacterium of the present invention, the activity of the microorganism (propionic acid bacterium) is stopped, and the quality does not change. Therefore, the prebiotics such as the culture of propionic acid bacteria of the present invention can stably maintain the immediate effect of intestinal regulation. That is, the culture of propionic acid bacteria of the present invention or the immediate-acting intestinal preparation containing the same is a prebiotic that acts even when killed, so that its production and quality control are easy. Furthermore, the preparations and the like based on the present invention can maintain their original activity (stability) over a long period even when stored at room temperature. In general, when the effect of oral administration is expected, it often depends on the action of living microorganisms (such as lactic acid bacteria and bifidobacteria), and the influence of gastric acid must be considered. This is because gastric acid reduces the number of viable microorganisms and a sufficient amount of viable bacteria cannot be delivered into the intestine. On the other hand, when the effect of oral administration is expected in the present invention, it does not depend only on the action of live propionic acid bacteria, it is not necessary to consider the effects of gastric acid, and the culture of propionic acid bacteria is sufficient. An immediate intestinal effect can be achieved.

The culture of propionic acid bacteria of the present invention or the sterilized product thereof can be processed into any form such as liquid, paste, gel, powder, granule, solid and the like. For example, an appropriate excipient is added (mixed) to the culture of the propionic acid bacterium of the present invention or the sterilized product thereof to adjust the solid content concentration to 30% to 40%, followed by spray drying or freeze drying. And can be pulverized. Here, known excipients can be used, for example, skim milk powder, whey powder, raw starch, dextrin, etc., and in addition, WPC, WPI, modified starch, etc. are used as necessary. be able to. And a publicly known method can be used for spray drying and freeze drying, for example, a method of spray-drying or freeze-drying a culture of the propionic acid bacterium of the present invention or a sterilized product thereof as it is, Alternatively, the culture of the propionic acid bacterium of the present invention, or a sterilized product thereof and a reducing solution of excipients are mixed and concentrated to a solids concentration of 30% to 40%, followed by spray drying or freeze drying. A method can also be used. Further, when filling the packaging material or container with the culture of the propionic acid bacterium of the present invention or the dried product (powder, granule, etc.) of the sterilized product, oxygen removal treatment (addition of nitrogen, addition of oxygen scavenger, etc.) ) Can be stored stably over a long period of time. In addition, it can be processed into a triturated preparation (0.2% powdered powder) for easy use in foods. As the modified starch of excipient, for example, in addition to dextrin, acetylated adipic acid cross-linked starch, acetylated phosphoric acid cross-linked starch, acetylated oxidized starch, octenyl sodium succinate starch, acetic acid starch, oxidized starch, hydroxypropyl starch Hydroxypropylated phosphoric acid crosslinking starch, phosphoric acid monoesterified phosphoric acid crosslinking starch, phosphorylated starch, phosphoric acid crosslinking starch and the like can be used. Moreover, the culture of the propionic acid bacterium of the present invention or the sterilized product thereof may be ingested together with the collagen peptide, or may be formulated together with the collagen peptide.

Generally, it is known that a culture of propionic acid bacteria has an effect of promoting the growth of lactic acid bacteria. A culture of propionic acid bacteria having such an action, or a processed product thereof (bacteria, concentrate, dried product, etc.) is also referred to as “Bifidogenic Growth Stimulator: BGS”. At this time, as long as this BGS has an immediate intestinal regulating effect, various components (such as raw materials) can be used as the culture of the propionic acid bacterium of the present invention.

As the culture of the propionic acid bacterium of the present invention, a whey fermentation product by the propionic acid bacterium is preferable. For example, reduced whey (aqueous whey powder solution) is fermented by Propionibacterium freudenreichii ET-3 producing BGS. The culture of propionic acid bacteria obtained in this way can be used (included) as an active ingredient in the rapid-acting intestinal regulating agent of the present invention. Such a culture of propionic acid bacteria containing BGS is also called “Profec”. At this time, this Profec specifically increases the number of bifidobacteria in the human intestine (Bifidobacterium 腸: 、 Bifidobacterium), so it has been approved as an ingredient involved in specific health foods (ILSI, No. 80, 5- 13 (2004)). BGSpowder (made by Meiji, trade name), tummy vitality tablet, and tummy vitality milk (made by Meiji, trade name; “tummy vitality” is a registered trademark of Tsubaki Meiji Co., Ltd.) are commercially available as a composition containing this “Profec”. ing. Therefore, “B.G.S.powder”, “tummy vitality tablet” or “tummy vitality milk” can also be used as the immediate-acting intestinal regulating agent of the present invention. In addition, it is well-known that the culture of propionic acid bacteria (whey fermented product by propionic acid bacteria) has an excellent intestinal effect that is manifested by continuous use over a long period of time. However, it has not been known that a culture of propionic acid bacteria, which is a prebiotic, has an excellent immediate-effect intestinal effect that is manifested in short-term use.

BGS contained in Profec includes, for example, 1,4-dihydroxy-2-naphthoic acid; 1,4-dihydroxy-2-naphthoic acid (DHNA), and 2-amino-3-carboxy-1,4- Naphthoquinone; 2-amino-3-carboxy-1,4-naphthoquinone (ACNQ). This DHNA is a biosynthetic intermediate of vitamin K2 (menaquinone) in microorganisms. These DHNA and ACNQ promote the growth of bifidobacteria by efficiently reoxidizing NADH produced during the metabolic process of bifidobacteria energy. Therefore, any of the following components (i), (i ′) and (ii), (ii ′), or two or more thereof can be used as the culture of the propionic acid bacterium of the present invention. That is, the present invention provides either (i) 1,4-dihydroxy-2- naphthoic acid (DHNA) and (ii) 2-amino-3-carboxy-1,4-naphthoquinone (ACNQ) or both. Provided is an immediate-acting intestinal adjusting agent containing as an active ingredient.

DHNA and ACNQ production methods have already been established, and those skilled in the art can easily synthesize and obtain them based on known literatures. This DHNA can be synthesized, for example, according to the method described in JP-A-2007-284449, but is not limited thereto. In addition, this ACNQ can be synthesized according to the methods described in, for example, JP-A No. 07-289273, Japanese Patent No. 3265193, Japanese Patent No. 2003-089683, Japanese Patent No. 4072430, Japanese Patent No. 3532226, but is not limited thereto. Therefore, these DHNAs and ACNQs can be used as they are as the immediate-acting intestinal regulating agent of the present invention by blending these synthesized products or fractions of the active ingredients thereof. Alternatively, these DHNA and ACNQ can be purified and used as the rapid-acting intestinal regulating agent of the present invention.

The present invention also provides an immediate-acting intestinal preparation containing as an active ingredient either (i ′) an analog of DHNA and (ii ′) an analog of ACNQ, or both. These analogs of DHNA and ACNQ include 1, 4-naphthoquinone, 2-methyl-1, 4-naphthoquinone, 4-amino-2-methyl-1-naphthol, 2-amino-3-chloro-1, Examples thereof include, but are not limited to, 4-naphthoquinone. These DHNA analogs and ACNQ analogs are known to be produced in cultures of microorganisms used for the production of fermented milk, for example, according to the method described in JP-A-07-289273. . Therefore, these DHNA analogs and ACNQ analogs can be used as they are as the rapid-acting intestinal regulating agent of the present invention by blending the culture of these microorganisms or fractions of the active ingredients thereof. Alternatively, the DHNA analog and ACNQ analog can be purified and used together with DHNA and ACNQ as the immediate-acting intestinal adjuster of the present invention.

In the rapid-acting intestinal preparation of the present invention containing the above components (i) and (i ′) and / or (ii) and (ii ′), the daily dose (ingestion amount) for humans (adults) Is generally in the range of 0.01 μg / kg · body weight to 100 mg / kg · body weight, using the converted amount (intake amount) of DHNA or an analog thereof contained in the culture of propionic acid bacteria as an index. However, in the rapid-acting intestinal preparation of the present invention, the daily dose (ingestion amount) for humans (adults) may be sufficient even if the dose is less than this, depending on the age, physique, sex, etc. of humans. Conversely, higher doses may be required. In the immediate-acting intestinal preparation of the present invention, the daily intake (dose) is not particularly limited, but for example, 5 μg or more (for example, 5 μg) using the converted amount (intake) of DHNA or an analog thereof as an index. To 100 μg), preferably 6 μg or more (for example, 6 μg to 50 μg), more preferably 6.5 μg or more (for example, 6.5 μg to 20 μg). And in the immediate action intestinal adjuster of the present invention, the daily intake (dose) is, for example, 0.5 mg or more (for example, 0.5 mg) using the converted amount (intake) of the culture of propionic acid bacteria as an index. ˜10 mg), preferably 0.6 mg or more (0.6 mg to 5 mg), more preferably 0.65 mg or more (0.65 mg to 2 mg).

In the rapid-acting intestinal preparation of the present invention containing the above components (i) and (i ′) and / or (ii) and (ii ′), the content per packaging form for humans (of adults) is, for example, In general, the converted amount (content) of DHNA or an analog thereof contained in the culture of propionic acid bacteria is used as an index, and generally ranges from 0.01 μg / kg · body weight to 100 mg / kg · body weight. However, in the immediate-acting intestinal adjuster of the present invention, the content per packaging form for humans (adults) may be sufficient even if it is less than this depending on the age, physique, gender, etc. of humans. In some cases, higher doses may be required. In the immediate-acting intestinal preparation of the present invention, the content per packaging form is not particularly limited. For example, 5 μg to 100 μg, preferably 6 μg to 50 μg, using the converted amount (content) of DHNA or an analog thereof as an index. More preferably, it is 6.5 μg to 20 μg. In the immediate-acting intestinal preparation of the present invention, the content per packaging form is, for example, 0.5 mg to 10 mg, preferably 0.6 mg to 5 mg, using the converted amount (content) of the culture of propionic acid bacteria as an index. More preferably, it is 0.65 mg to 2 mg.

In the rapid-acting intestinal preparation of the present invention, the administration frequency (intake frequency) for humans (adults) can be divided into several times (eg 2 to 4 times) per day, for example. The daily dose (ingestion amount) for humans (adults) means the amount necessary to develop an immediate effect of intestinal regulation, and the person (ingestion) of human age, physique, gender, etc. And the like, the administration route, the degree of intestinal effect expected actually, and the like. At this time, in the rapid-acting intestinal preparation of the present invention, the administration route (intake route) for human (adult) is preferably oral administration (oral intake) or enteral administration (enteral intake), and oral administration (oral intake). Is more preferable.

The rapid-acting intestinal preparation of the present invention can be prepared by blending a culture of propionic acid bacteria at, for example, 0.001 to 20% by weight, preferably 0.01 to 15% by weight, more preferably 0.05 to 10% by weight. . The rapid-acting intestinal regulating agent of the present invention can be processed into any dosage form such as liquid, paste, gel, powder, granule, solid and the like. Specifically, it can be formulated into tablets, capsules, granules, powders, syrups and the like. In these various preparations, the main ingredients are excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspending agents, coating agents, solvents, isotonic agents, antioxidants, stabilization. It can be formulated according to a conventional method while applying known additives that can be usually used in the pharmaceutical formulation technical field such as an agent (for example, vitamin C). The rapid-acting intestinal preparation of the present invention is prepared by blending (mixing) propionic acid bacteria with components (milk fermentation components, etc.) suitable for oral administration (oral intake), pharmaceutically acceptable carriers, and the like. And can be provided. Alternatively, the immediate-acting intestinal adjuster of the present invention is obtained by adding (dispersing) a propionic acid bacterium culture to a component (such as a milk fermentation component) suitable for oral administration (oral intake), a pharmaceutically acceptable carrier, or the like. Can also be prepared and provided. At this time, vitamins, minerals, organic acids (including fatty acids such as short chain fatty acids), saccharides, amino acids, peptides (for example, collagen peptides) and the like can be blended in appropriate amounts.

As described above, the present inventors selected (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, and (c) at least one component selected from the group consisting of ACNQ or an analog thereof. It has been found that immediate intestinal regulating effects are expressed in ingested (oral administration, etc.) humans. That is, the present invention comprises (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, (c) at least one component selected from the group consisting of ACNQ or an analog thereof, It relates to an intestinal regulating agent.

In addition, the present invention provides an animal ingesting (orally) at least one component selected from the group consisting of (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, and (c) ACNQ or an analog thereof. And the like, and the like. In the present invention, examples of animals include mammals, birds, amphibians, and reptiles, but mammals are preferred, humans are more preferred, and humans are even more preferred.

The present invention also relates to a rapid-acting intestinal agent of at least one component selected from the group consisting of (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, and (c) ACNQ or an analog thereof. For use in manufacturing. Alternatively, the present invention provides an immediate-acting intestinal adjustment of at least one component selected from the group consisting of (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, and (c) ACNQ or an analog thereof. It relates to use in the manifestation of effects. In addition, the present invention comprises a step of using at least one component selected from (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, and (c) ACNQ or an analog thereof. The present invention relates to a method for producing a sex adjusting agent. Furthermore, the present invention is a group comprising (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, (c) ACNQ or an analog thereof for use in the development of an immediate effect of regulating the intestine. Relates to at least one component selected.

The immediate-acting intestinal agent of the present invention includes pharmaceuticals, quasi drugs, health supplements, health functional foods (specific health foods or nutritional functional foods), functional foods (supplements, etc.), other foods, food additives, etc. It can be used in the form of In supplements and the like, for example, a tablet is a preferable form from the viewpoint of good storage stability and the ability to reliably take an effective amount. In this specification, “food” includes “beverage”. Furthermore, the rapid-acting intestinal adjuster of the present invention can also be used in biological standards of pharmaceuticals, foods and drinks (foodstuffs such as infant formulas, infant formulas, and lactating formulas). Examples of the rapid-acting intestinal adjuster of the present invention include various propionic acid bacteria suspensions, propionic acid bacteria, propionic acid culture supernatant (including medium components), propionic acid fermentation products, and the like. Can be included.

The immediate-acting intestinal adjuster of the present invention can be ingested alone (oral administration), or can be ingested (oral administration) in combination (mixed) with other components commonly used in pharmaceuticals and foods. . At this time, particularly when used in combination with other compounds or microorganisms having an intestinal effect, it is effective in the expression and improvement of the immediate effect of intestinal effect.

The immediate-acting intestinal preparation of the present invention includes milk, dairy products, soft drinks, powdered drinks, fermented milk, lactic acid bacteria drinks, acidic drinks, yogurt, cheese, bread, biscuits, crackers, pizza crusts, formula milk powder, Examples include liquid foods, foods for patients, nutritional foods, frozen foods, food compositions, processed foods, and other commercially available foods. The immediate-acting intestinal adjuster of the present invention can be set to, for example, a pH of 2 to 6, preferably 3 to 5, as an acidic pharmaceutical or food form.

The immediate-acting intestinal regulating agent of the present invention, as shown in the Examples described later, exhibited an immediate-acting intestinal regulating effect when ingested as an ingredient of a culture of propionic acid bacteria. Accordingly, the present invention provides a functional food containing at least one component selected from the group consisting of (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, and (c) ACNQ or an analog thereof. Or let a pharmaceutical composition be one of the preferable aspects.

That is, the present invention provides at least one component selected from the group consisting of (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, and (c) ACNQ or an analog thereof, as a functional food or a pharmaceutical. The present invention relates to a method for producing a functional food or a pharmaceutical composition that expresses an immediate effect of regulating the intestine, including a step of blending with a chemically acceptable carrier. Alternatively, the present invention includes, in a functional food, at least one component selected from the group consisting of (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, and (c) ACNQ or an analog thereof. The present invention relates to a method for imparting a functional food with the ability to develop an immediate effect of regulating the intestine, including the step of:

In addition, the present invention provides pharmaceutically acceptable at least one component selected from the group consisting of (a) a culture of propionic acid bacteria, (b) DHNA or an analog thereof, and (c) ACNQ or an analog thereof. A pharmaceutical composition prepared by blending with a carrier. Furthermore, when an additional component (for example, collagen peptide) is blended, it can be prepared by mixing saccharides (for example, maltodextrin) and the like homogeneously as a carrier, and blended with vitamin C and the like as a stabilizer. May be. The immediate action intestinal agent of the present invention is a protein derived from a culture of propionic acid bacteria, for example, 1% by weight or more of saccharides, preferably 10% by weight or more of saccharides, more preferably 30% by weight or more of saccharides. More preferably, it can be prepared by blending so that the ratio is 70% by weight or more of the saccharide. Furthermore, the immediate-acting intestinal adjuster of the present invention should be set to, for example, 0.1 to 3 kcal, preferably 0.3 to 2.5 kcal, more preferably 0.5 to 2 kcal per mL as a form of a pharmaceutical enteral nutrient or liquid food. Can do.

Note that all prior art documents cited in this specification are incorporated herein by reference.

Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to the following examples.

(1) Subjects The subjects were 76 Thai women aged 18 to 49 years with mild constipation (slow or irregular bowel movements). Subject characteristics are shown in Table 1 (numbers are average values ± standard deviation).

(2) Test meal 1.5 g / pack of BGS powder (composition containing Profec, dextrin and glucose) was used as the test meal. Profec is a composition in which whey is fermented with Propionibacterium freudenreichii ET-3 (propionic acid bacterium ET-3) and then sterilized. One BGS powder (1.5 g) contained DHNA (1,4-dihydroxy-2-naphthoic acid) in an amount of 6.5 μg to 6.6 μg.

(3) Test schedule The subject ingested the test meal (BGS powder) at 1 packet / day at any time. During the first two weeks (Week 1 and Week 2) of the start of the study, the subjects did not take the test meal during the pre-intake period (pre-intake period) and in the next 2 weeks (Week 3 and Week 4) During the ingestion period (intake period), the subject took the test meal, and in the next two weeks (Week 5, Week 6), the subject took the test meal as the period after ingestion (post intake period). Did not take.

(4) Survey method “Frequency of defecation”, “Defecation difficulty”, “Defecation time” for each BEG powder before / during / after ingestion once a week using the specified questionnaire form , "Defecation satisfaction" was investigated.

(5) Restrictions During the study, yogurt intake, alcohol intake, and intestinal treatment were prohibited.

(6) Survey results (6-1) Changes in defecation frequency (defecation frequency, defecation amount) The results of changes in defecation frequency (defecation frequency, defecation amount) are shown in FIG. 1, FIG. 2, and FIG. According to FIG. 1, in the “intake period” in which the test subject ingests the test meal, the “number of defecations” significantly increased. And in the “post-intake period” when the subject stopped taking the test meal, the “frequency of defecation” tended to decrease compared to the “intake period”, but the subject did not take the test meal. Compared with the “pre-ingestion period”, the “frequency of defecation” was maintained significantly higher.
Furthermore, according to FIG. 2 and FIG. 3, both the number of defecations (FIG. 2) and the amount of defecation (FIG. 3) every day, only 1 day (W3-1) from the start of intake of the test meal, There was a significant increase in both the “period” (Week 1 and Week 2) and the mean value for one week before intake (Week 2). On the second day (W3-2) after ingestion of the test meal, it increased more remarkably and remained high throughout the intake period.
From these results, the ingestion of the immediate-acting intestinal agent of the present invention shows that the effect of increasing the number of defecations and the amount of defecation (intestinal effect) is manifested in a short period of time, and the intestinal effect associated with the change is sustained. It became clear.

(6-2) Change in defecation difficulty The results of defecation difficulty are shown in FIG. In the “intake period”, immediately after ingestion of the test meal, the “difficulty of defecation” decreased, and the percentage of “no problems” increased. In the “post-ingestion period”, the “degree of defecation” tended to decrease compared to the “intake period”, but compared to the “pre-intake period”, the percentage of “no problem” responses It remained significantly higher.
From these results, the effect of improving defecation difficulty (intestinal effect) is manifested in a short period of time by ingesting the immediate-acting intestinal agent of the present invention, and the intestinal effect associated with the change is sustained. And it became clear that the physical burden was small.

(6-3) Change in defecation time The result of defecation time is shown in FIG. In the “intake period”, the percentage of respondents whose “defecation time” was “less than 5 minutes” increased significantly. In the “post-ingestion period”, the response rate of “less than 5 minutes” tended to decrease somewhat compared to the “intake period”, but compared to the “pre-intake period”, The percentage of “

(6-4) Change in sensation during defecation The results of sensation during defecation are shown in FIG. In the “intake period”, the frequency of abdominal pain, etc. decreased, and the proportion of respondents who replied “sense during defecation” as “normal” increased significantly. In the “post-ingestion period”, the percentage of responding “normal” tended to decrease compared to the “ingestion period”, but compared to the “pre-ingestion period”, the percentage of responding “normal” It remained significantly higher.
From these results, by taking the immediate action intestinal preparation of the present invention, the effect of improving the time required for defecation and the sensation during bowel movement (intestinal effect) is manifested in a short period of time, and the intestinal effect associated with the change is demonstrated. It became clear that it was persistent and the physical burden was small.

(6-5) Change in defecation satisfaction The results of satisfaction with the frequency of defecation are shown in Fig. 7, the results of satisfaction with the time required for defecation are shown in Fig. 8, and the results of satisfaction with the characteristics of defecation are shown. FIG. 9 shows the results of satisfaction with the defecation habit. With regard to the frequency of defecation, the time required for defecation, and the characteristics of defecation, the percentage of “very satisfied” and “satisfied” responses increased significantly in the “ingestion period”. The percentage of “very satisfied” and “satisfied” responses remained significantly higher.
From these results, the effect of improving the degree of satisfaction with bowel movement (intestinal effect) is manifested in a short period of time by ingesting the immediate action intestinal agent of the present invention, and the intestinal effect associated with the change is sustained. And it became clear that the physical burden was small.

(1) Subjects The subjects were 128 Japanese women aged 18 to 64 whose number of bowel movements was approximately 4 or less per week.

(2) Test meal 7 g of “Amino Collagen Profec” (manufactured by Meiji Co., Ltd.) was used as a test meal. “Amino Collagen Profec” is composed of fish collagen peptide (gelatin), maltodextrin, whey fermented product (milk-derived), vegetable oil, vitamin C, glucosamine, arginine, thickener (gum arabic), and flavoring. 7 g of “collagen profec” contained 6.6 μg or more of DHNA derived from the whey fermentation product.

(3) Test schedule The subjects took the test meal at 7 g / day for an arbitrary time for 25 days. Regarding the number of days after ingestion, the first ingestion day was defined as “Day 0”.

(4) Survey method After ingesting the test meal, the number of days after ingestion when the intestinal effect was felt was investigated.

(5) Survey results FIG. 11 and Table 2 show the distribution of the number of days after ingestion in which the subjects realized the effect of regulating the intestines. The day when the intestinal effect was first felt varied from immediately after ingestion to the 24th day after ingestion, but the most subjects who experienced the intestinal effect were on day 0 after ingestion, then 2 There were many in order of the 3rd day. In addition, as shown in FIG. 1 and Table 2, the cumulative proportion of subjects who realized the bowel regulation effect was found that more than half (about 54%) of the subjects felt the bowel regulation effect on the fourth day after ingestion and About 72% of the subjects on

day

6 and 80% or more (about 82%) of the intestinal effect realized on day 7 after ingestion. In addition, by the 24th day after ingestion, all the subjects felt the intestinal effect, and the average number of days when the intestinal effect was first felt was about 4.9 days.

The rapid-acting intestinal preparation containing the propionic acid bacteria culture provided as an active ingredient based on the present invention can exhibit an intestinal effect (especially an effect of improving bowel movement) in a short period of time by ingesting it. it can. The immediate-acting intestinal preparation of the present invention is composed of ingredients that have been proven to be excellent in safety and taste from a long dietary experience, have a low physical burden, and take it over a long period of time You can also.

Claims

An immediate intestinal regulating agent containing at least one component of a culture of propionic acid bacteria, or DHNA or an analog thereof.
The immediate-acting intestinal adjuster according to claim 1, wherein the propionic acid bacterium is Propionibacterium freudenreichii.
3. The rapid-acting intestinal regulating agent according to claim 1 or 2, which is a rapid-acting bowel movement improving agent.
The rapid-acting intestinal preparation according to any one of claims 1 to 3, wherein an effect of improving bowel movement is obtained within 7 days after ingestion.
The immediate-acting intestinal preparation according to any one of claims 1 to 4, wherein the effect of improving stool persists for 2 weeks after the withdrawal of intake.